S211: EFFICACY AND SAFETY OF ROPEGINTERFERON ALFA-2B FOR PRE-FIBROTIC PRIMARY MYELOFIBROSIS AND DIPSS LOW/INTERMEDIATE-1 RISK MYELOFIBROSIS: UPDATED RESULTS AND GENOMIC CHARACTERISTICS
Authors: Harry Gill, Lester Au, Dorothy Tsai, Man Kit Garret Leung, Rita Yim, Lynn Chin, Vivian LI, Paul Lee, Chung Fung Albert Sin, Hsin-An Hou, Chih-Cheng Chen, Yok Lam Kwong
Journal: HemaSphere (2023)

Background: Most patients with primary myelofibrosis (PMF) in early/pre-fibrotic stage (pre-PMF) with dynamic international prognostic scoring system (DIPSS) low or intermediate-1 risks progress to higher risks or overt MF. There is currently no consensus on the optimal treatment for these patients. Ropeginterferon alfa 2b (P1101) is a next-generation monopegylated interferon alfa-2b developed specifically to treat myeloproliferative neoplasms (MPN). Aims: P1101MF is an on-going multicenter phase 2 study of P1101 in patients with pre-PMF and DIPSS low/intermediate-risk PMF. Methods: Key eligibility included morphologically confirmed pre-PMF, overt PMF, post-polycythemia vera MF (PPV-MF) or post-essential thrombocythaemia MF (PET-MF), DIPSS low/intermediate-1 risks, and the need for cytoreduction. The primary outcome were haematologic responses at 24 and 48 weeks. Secondary outcomes included adverse events (AEs), changes in allele burden of driver and non-driver gene mutations, quality-of-life (QOL), cytokine profiles and bone marrow morphology. Patients received P1101 at a starting dose of 250mcg followed by 350mcg at week 2 and 500mcg every 2 weeks from week 4 onwards. Results: At the data cut-off of 27 February 2023, 36 men and 26 women with a median age of 59 (range: 30-86) years were enrolled. Case distribution was pre-PMF, N=44 (71%): overt PMF, N=6 (9.7%);PPV-MF, N=5 (8.1%); and PET-MF, N=7 (11.3%). Mutational profile of driver genes was JAK2V617F, N=43 (69.4%); CALR mutations (Type 1/type-1 like, N=13; Type 2/type 2-like, N=4), MPL mutation, N=1 (1.6%). Next-generation sequencing (NGS) of non-driver mutations showed haboured high molecular risk mutations, N=8 (12.9%)(ASXL1, N=3; EZH2, N=2; IDH2, N=2; SFSF2, N=1). One triple-negative pre-PMF case showed the TP53 p.Arg248Gln variant. The median time from diagnosis to treatment was 5 months (range: 1-266 months). At baseline, the median white blood cell count (WBC), haemoglobin (Hb), platelet count, and lactate dehydrogenase were 7 x 109/L (range: 3.3-33.95 x 109/L), 12.6 g/dL (range: 7.1-15.9 g/dL), 500 x 109/L (range: 113-1114 x 109/L) and 277 IU/L (range: 136-1146) respectively. The baseline median MPN Symptom Assessment Form Total Symptom Score was 16 (range:0-49). The median follow-up was 55 (9-61) weeks, with 56 patients (90%) and 35 patients (56%) having completed 24 and 48 weeks of treatment respectively. At 24 weeks, responses in Hb (defined as 10g/dL to upper limit normal), WBC (WBC < 10 x 109/L) and platelet (defined as platelet count ≤ 400 x 109/L) were 76.6%, 87.2% and 78.7% respectively. Furthermore, 36 (92%) of 39 evaluated JAK2V617F mutated patients had stable or improved JAK2V617F allele burden by droplet digital polymerase reaction. Three patients (8%) had >50% reduction in the JAK2V617F allele burden with one patients achieving undetectable JAK2V617F from week 16 onwards. There were 3 discontinuations (personal reasons, N=2; symptom progression, N=1). None of the pre-PMF cases progressed to overt PMF. Progression to blast phase was not observed. The most common AEs were malaise (N=29, 47%; Grade 1-2, N=28; Grade 3-4, N=1), anaemia (N=26, 42%; Grade 1-2, N=22; Grade 3-4, N=4), and hair loss (N=23, 37%; Grade 1-2, N=23; Grade 3-4; N=0). Eight patients (13%) had asymptomatic derangement thyroid function. Neuropsychiatric disorders and other autoimmune disorders were not observed. Summary/Conclusion: In summary, P1101 was generally well-tolerated, effective in cytoreduction and induced molecular responses early in JAK2V617F-mutated patients with pre-PMF and low/intermediate-1-risk PMF. Keywords: Ropeg-Interferon, Myelofibrosis